Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately😕. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell-fate in colorectal cancer (CRC), we performed a systematic single-cell analysis of 1,071 colonic organoid cultures regulated by…

A Single-cell Perturbation Landscape of Colonic Stem Cell Polarisation

Qin et.al | bioRxiv | 2023.02.15.528008 | doi: https://doi.org/10.1101/2023.02.15.528008

Author

Leader: Christopher J. Tape | UCL Cancer Institute

Focus on: How the different cell types in cancer communicate with one another to drive tumours

Work with: Organoid | scRNA-Seq | sc-MS

Website: The Cell Communication Lab: http://tape-lab.com/

Background

Intestinal cell type:

Ref

1. intestinal stem cells and epithelium cells:
   2021, Nat Rev Mol Cell Biol
   2019, Nat Rev Gastroenterol Hepatol
   2010, Transl Res
   2021, Cell Regen
   
2. intestinal mesenchymal cells:
   2020, Nat Cell Biol
   2020, Immunology
   2022, Int J Mol Sci
   
3. intestinal immune cells:
   2014, Nat Rev Immunol
   
4. intestinal neural cell:
   2021, Front Physiol
   2022, Nat Rev Gastroenterol Hepatol
   
5. intestinal single cell atlas:
   2021, Nature
   2021, Cell
   

1. Intestinal stem cell (ISC):

• i. Crypt base columnar (CBC) cells: canonical/traditional/rapidly-cycling stem cell | generation of multiple lineages and long-term self-renewal | bottom of the crypt; interspersed between Paneth cells | LGR5+ OLFM4+
• ii. +4 cells/Label-retaining cells (LRC): reserved/precursor/quiescent stem cell population 2013, Nature | +4 means located at the ~+4 from the crypt base;label-retaining means take advantage of these cells slow-cycling characteristic to take LRC approach (e.g. EdU labeling), a lineage tracing method, and LRCs are cells that retain a DNA synthesis label after a prolonged chase period | committed to mature into Paneth cells and EECs, but retain the ability to reacquire stem-cell function. At homeostatic/normal intestinal tissue they do not contribute cell turnover but can repopulate the crypt upon damage.

2. progenitor cells:

also named as transit-amplifying cells(TACs) (not accurate) | more specific than stem cells and can only be pushed to differentiate into its “target” cell type.

Adult stem cells usually reside in a specialized niche microenvironment (niche cells and the niche signals they produce), which provides necessary extracellular signals and substances to promote the long-term maintenance and self-renewal of stem cells

The epithelium and mesenchyme cooperate to generate the complex dynamic observed in intestinal crypts. Together they provide the key signals that regulate intestinal fate determination: WNT, Notch, EGF and BMP signalling

3. epithelium cell:

epithelium cell (especially Paneth cell) constitute the epithelial niche
Ref:
2022, Cell Mol Gastroenterol Hepatol
2017, Nature

• i. Secretory lineage
  • (1) Paneth cells:
  • (2) Goblet cells
  • (3) Enteroendocrine cells (EEC)
  • (4) Tuft cells
• ii. Absorptive lineage
  • (1) Enterocytes
  • (2) M cells

here is epithelium cell specification:

4. Intestinal mesenchymal (stromal) cell (IMC):

1. Naming ambiguity: mesenchymal cell (MC) or stromal cell | mesenchymal stem cell (MSC) or mesenchymal stromal cell😤
   
2. cancer-associated transdifferentiation: transdifferentiation of epithelial cells to mesenchymal cells (EMT); transdifferentiation of endothelial to mesenchymal cells (EndMT); transdifferentiation of mesothelial cells to mesenchymal cells (MMT)
   
3. Most of IMC originates from the mesoderm and differentiates from mesenchymal stem cells, locate on subepithelial compartment, constitute the mesenchymal niche.
   NOTE: for CRC IMC, here is a review:2017, Gastroenterology
   
4. subtypes:
   Warning

   Here is an unclear part, most people think mesenchymal cell represent a non-hematopoietic, non-epithelial, and non-endothelial stromal compartments of connective tissues. They include highly diverse populations of fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesenchymal progenitor cells, but Mesothelial cells is what?
   pericyte; myofibroblasts (telocytes); fibroblast; xxx fibroblast…; myocytes (smooth muscle cells / muscularis).. (Foxl1+ MCs; Gli1+ MCs…)
   
   A reasonable classification:
   

   

5. Other cell types:

• i. Immune cells: ..
  
• ii. Endothelial cells:
  
• iii. Mesothelial cells: some papers seem classify mesothelial cells as mesenchymal (stromal) cell..?😤
  
• iv. intestinal neural cells: intestinal has its typical nervous system called intrinsic enteric nervous system (ENS): neuron and enteric glial cells (EGC)…
  …